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PubMed2005

Leishmania tropica in northern Israel: a clinical overview of an emerging focus.

BACKGROUND: In Israel, most cutaneous leishmaniasis (CL) is caused by Leishmania major. Recently a new focus of CL caused by Leishmania tropica has been described in Tiberias and the surrounding area of northern Israel. OBJECTIVE: The aim of this study was to evaluate clinical (size, number, location, and type of lesion) and laboratory (culture and polymerase chain reaction [PCR] analysis) parameters at diagnosis, response to treatment, and outcome of patients with CL due to L tropica. METHODS: Between September 2002 and March 2004, patients with direct smear-confirmed CL were evaluated; clinical records were reviewed and a telephone survey was performed. RESULTS: Forty nine patients, 34 (69%) male and 15 (31%) female, were studied. Mean age was 31.1 years (median 26 years, range 1-70); 76% of patients live in Tiberias and the surrounding area. The mean number of lesions was 2.6 (median 2, range 1-10). Lesions were commonly located on the face (61%) and upper limbs (57%). PCR analysis was performed in 27 patients and was positive for L tropica in 26. Fifty percent of patients studied received multiple therapeutic regimens because of incomplete response or treatment failure. Topical paromomycin was used in 44 patients (90%), with a complete response reported in only 17 (39%); of the 9 patients treated with intralesional sodium stibogluconate, a complete response was reported in 6 (67%); of the 5 patients treated with intravenous sodium stibogluconate, 4 (80%) were cured. LIMITATIONS: The relatively small number of patients studied combined with the fact that some were assessed retrospectively limit our conclusions. In addition, 50% of the patients studied received multiple therapeutic regimens because of failure of, or incomplete responses to, their initial therapy, thereby making comparisons difficult. CONCLUSIONS: The cure rate in those completing a course of antimony therapy, either 10 or more days of intravenous therapy or therapy administered intralesionally, was 75% (95% confidence interval [CI], 50.5-99.5%) as compared with 45% (95% CI, 28.9-60.5%) among those completing at least 10 days of topical paromomycin. To date, no standardized, simple, safe, and highly effective regimen for treating L tropica exists. Large, controlled clinical trials to evaluate current treatment regimens as well as new medications for CL, and especially CL attributed to L tropica, are urgently needed.

Adolescent↗
PubMed2004

The efficacy of some drugs with known antiprotozoal activity against Histomonas meleagridis in chickens.

Nine drugs with known or suspected antiprotozoal activity were tested in vitro, and in vivo for activity against Histomonas meleagridis. The nitroimidazoles dimetridazole, metronidazole, ornidazole, and tinidazole suppressed growth of H. meleagridis in vitro at 10 microg/ml or higher. Paromomycin sulfate, and carbadox were weakly effective at high levels. Quinolinol, mebendazole, diloxanide furoate, and albendazole had no demonstrable efficacy in vitro. Drugs showing some activity in vitro were tested in young chickens inoculated intracloacally with 2 x 10(5) H. meleagridis/bird. Dimetridazole, metronidazole, ornidazole, and tinidazole were highly effective at 200 ppm in feed. Paromomycin sulfate, and carbadox were ineffective in vivo, with no improvement in liver or cecal lesion scores compared to that of infected controls. Thus, the only new entities with efficacy against blackhead disease in vivo were nitroimidazoles, related to the positive control dimetridazole.

Animals↗
PubMed2006

Molecular contacts between antibiotics and the 30S ribosomal particle.

Crystal structures of complexes between ribosomal particles and antibiotics have pinned down very precisely the discrete binding sites of several classes of antibiotics inhibiting protein synthesis. The crystal structures of complexes between various antibiotics and ribosomal particles show definitively that ribosomal RNAs (rRNAs), rather than ribosomal proteins, are overwhelmingly targeted. The antibiotics are found at messenger RNA or transfer RNA binding sites and, most importantly, at pivot locations that are key for the structural rearrangements during the molecular mechanical steps in initiation, elongation, or termination of protein synthesis. We focus here on the 30S particle. Structurally, the antibiotics interact in many ways with RNA: (i) only with the phosphate groups (streptomycin); (ii) mainly with bases (hygromycin, spectinomycin); (iii) with a mixture of both (paromomycin, Geneticin); (iv) via magnesium ions (tetracycline) or a protein side chain (streptomycin). The antibiotics can mimic base stacking (pactamycin) or form pseudo-base pairing interactions with ribosomal bases (paromomycin and related aminoglycosides). Resistance strategies (mutations or methylations in rRNA or enzymatic modifications of the antibiotics) can generally be understood on the basis of the intermolecular contacts made between the antibiotics and rRNA residues in the crystal structures. In humans, toxicity of ribosomal antibiotics is most likely due, at least in part, to the sensitivity of mitochondrial ribosomes, since mitochondria evolved from a bacterial ancestor. Antibiotic families (e.g., aminoglycosides) form a set of invariant H-bonds to defined rRNA residues. When such residues are conserved in bacteria, but not in eukaryotes, resistance of eukaryotic ribosomes is observed. The structural knowledge, together with comparative genomic analysis, should allow for the development of new broad-spectrum antibiotics with higher selectivity toward bacterial ribosomes and less toxicity on eukaryotic cytoplasmic and mitochondrial ribosomes.

Aminoglycosides↗
PubMed1999

Prodigious substrate specificity of AAC(6')-APH(2"), an aminoglycoside antibiotic resistance determinant in enterococci and staphylococci.

BACKGROUND: High-level gentamicin resistance in enterococci and staphylococci is conferred by AAC(6')-APH(2"), an enzyme with 6'-N-acetyltransferase and 2"-O-phosphotransferase activities. The presence of this enzyme in pathogenic gram-positive bacteria prevents the successful use of gentamicin C and most other aminoglycosides as therapeutic agents. RESULTS: In an effort to understand the mechanism of aminoglycoside modification, we expressed AAC(6')-APH(2") in Bacillus subtilis. The purified enzyme is monomeric with a molecular mass of 57 kDa and displays both the expected aminoglycoside N-acetyltransferase and O-phosphotransferase activities. Structure-function analysis with various aminoglycosides substrates reveals an enzyme with broad specificity in both enzymatic activities, accounting for AAC(6')-APH(2")'s dramatic negative impact on clinical aminoglycoside therapy. Both lividomycin A and paromomycin, aminoglycosides lacking a 6'-amino group, were acetylated by AAC(6')-APH(2"). The infrared spectrum of the product of paromomycin acetylation yielded a signal consistent with O-acetylation. Mass spectral and nuclear magnetic resonance analysis of the products of neomycin phosphorylation indicated that phosphoryl transfer occurred primarily at the 3'-OH of the 6-aminohexose ring A, and that some diphosphorylated material was also present with phosphates at the 3'-OH and the 3"'-OH of ring D, both unprecedented observations for this enzyme. Furthermore, the phosphorylation site of lividomycin A was determined to be the 5"-OH of the pentose ring C. CONCLUSIONS: The bifunctional AAC(6')-APH(2") has the capacity to inactivate virtually all clinically important aminoglycosides through N- and O-acetylation and phosphorylation of hydroxyl groups. The extremely broad substrate specificity of this enzyme will impact on future development of aminoglycosides and presents a significant challenge for antibiotic design.

Acetylation↗
PubMed1984

Fidelity of the eukaryotic codon-anticodon interaction: interference by aminoglycoside antibiotics.

A homologous in vitro method was developed from Tetrahymena for ribosomal A-site binding of aminoacyl-tRNA to poly(uridylic acid)-programmed ribosomes with very low error frequency. The reaction mixture pH was the crucial factor in the stable A-site association of aminoacyl-tRNA with high fidelity. At a pH greater than 7.1, endogenous activity translocated A-site-bound aminoacyl-tRNA to the P site. If translocation was allowed to occur, a near-cognate amino-acyl-tRNA, Leu-tRNA, could stably bind to the ribosome by translocation to the ribosomal P site. Near-cognate aminoacyl-tRNA did not stably bind to either site when translocation was blocked. Misreading antibiotics stimulated the stable association of near-cognate aminoacyl-tRNA to the ribosomal A site, thereby increasing the error frequency by several orders of magnitude. Ribosome binding of total aminoacyl-tRNA near equilibrium was not inhibited by misreading antibiotics; however, initial rate kinetics of the binding reaction were dramatically altered such that a 6-fold rate increase was observed with paromomycin or hygromycin B. The rate increase was evident with both cognate and near-cognate aminoacyl-tRNAs. Several antibiotics were tested for misreading potency by the ribosome binding method. We found gentamicin G418 greater than paromomycin greater than neomycin greater than hygromycin B greater than streptomycin in the potentiation of misreading. Tetracycline group antibiotics effectively inhibited A-site aminoacyl-tRNA binding without promoting misreading.

Animals↗
PubMed1999

Determinants of aminoglycoside-binding specificity for rRNA by using mass spectrometry.

We have developed methods for studying the interactions between small molecules and RNA and have applied them to characterize the binding of three classes of aminoglycoside antibiotics to ribosomal RNA subdomains. High-resolution MS was used to quantitatively identify the noncovalent binding interactions between mixtures of aminoglycosides and multiple RNA targets simultaneously. Signal overlap among RNA targets was avoided by the addition of neutral mass tags that direct each RNA target to a unique region of the spectrum. In addition to determining binding affinities, the locations of the binding sites on the RNAs were identified from a protection pattern generated by fragmenting the aminoglycoside/RNA complex. Specific complexes were observed for the prokaryotic rRNA A-site subdomain with ribostamycin, paromomycin, and lividomycin, whereas apramycin preferentially formed a complex with the eukaryotic subdomain. We show that differences in binding between paromomycin and ribostamycin can be probed by using an MS-MS protection assay. We have introduced specific base substitutions in the RNA models and have measured their impact on binding affinity and selectivity. The binding of apramycin to the prokaryotic subdomain strongly depends on the identity of position 1408, as evidenced by the selective increase in affinity for an A1408G mutant. An A1409-G1491 mismatch pair in the prokaryotic subdomain enhanced the binding of tobramycin and bekanamycin. These observations demonstrate the power of MS-based methods to provide molecular insights into small molecule/RNA interactions useful in the design of selective new antimicrobial drugs.

Aminoglycosides↗
PubMedDate not supplied

In vitro evaluation of antimicrobial compounds for cysticidal activity against Acanthamoeba.

Amebic keratitis presents a therapeutic dilemma because Acanthamoeba, unlike Naegleria, encysts in infected tissues. To date, the results of medical therapy have been disappointing, and the optimal medical regimen for acanthamoeba keratitis is yet to be defined. Clinical cure necessitates eradication of the encysted amebae with medications known to have ocular toxic effects in combination with surgical maneuvers. Antiinfective agents possessing in vitro cysticidal activity include paromomycin, neomycin, ketoconazole, natamycin, and ciclopirox olamine, but no agent has been shown to be uniformly effective against all isolates of Acanthamoeba. Treatment of amebic cysts with propamidine isethionate plus either paromomycin or neomycin has produced slightly additive cysticidal effects. Multiple factors, including the varied clinical presentation and the lack of standardized in vitro techniques for the assay of cysticidal activity, account for the lack of correlation between in vitro activity and in vivo efficacy.

Acanthamoeba↗
PubMed1976

Tobramycin adenylyltransferase: a new aminoglycoside-inactivating enzyme from Staphylococcus epidermidis.

Certain strains of Staphylococcus epidermidis resistant to the aminoglycoside antibiotics were shown to contain an enzyme that inactivates the kanamycins, neomycins, butirosins, paromomycin, gentamicin A, amikacin, and tobramycin by adenylylation. Tobramycin adenylyltransferase, as this enzyme is called, was found to be optimally active at pH 5.5. With paromomycin or neomycin B and C as substrates, however, two pH values (5.5 and 9.0) for optimal activity were observed. The enzyme requires Mg++ for activity and is stabilized significantly by dithiothreitol. It is probable that the 4'-hydroxyl group of ring I of the antibiotics is adenylylated. Those aminoglycosides that are not substrates for the enzyme lack a hydroxyl group in the corresponding position.

Adenosine Triphosphate↗
PubMed2000

Agrobacterium rhizogenes-mediated transformation of opium poppy, Papaver somniferum l., and California poppy, Eschscholzia californica cham., root cultures.

An efficient protocol for the establishment of transgenic opium poppy (Papaver somniferum L.) and California poppy (Eschscholzia californica Cham.) root cultures using A. grobacterium rhizogenes is reported. Five strains of A. rhizogenes were tested for their ability to produce hairy roots on wounded opium poppy seedlings and California poppy embryogenic calli. Three of the strains induced hairy root formation on both species, whereas two others either caused the growth of tumorigenic calli or produced no response. To characterize the putative transgenic roots further, explant tissues were co-cultivated with the most effective A: rhizogenes strain (R1000) carrying the pBI121 binary vector. Except for the co-cultivation medium, all formulations included 50 mg l(-1) paromomycin to select for transformants and 200 mg l(-1) timentin to eliminate the Agrobacterium. Four weeks after infection, paromomycin-resistant roots appeared on 92-98% of explants maintained on hormone-free medium. Isolated hairy roots were propagated in liquid medium containing 1.0 mg l(-1) indole-3-acetic acid to promote rapid growth. Detection of the neomycin phosphotransferase gene, high levels of beta-glucuronidase (GUS) transcripts and enzyme activity, and GUS histochemical localization confirmed the integrative transformation of root cultures. Transgenic roots grew faster than wild-type roots, and California poppy roots grew more rapidly than those of opium poppy. With the exception of a less compact arrangement of epidermal cells and more root hairs, transformed roots of both species displayed anatomical features and benzylisoquinoline alkaloid profiles that were virtually identical to those of wild-type roots. Transgenic root cultures of opium poppy and California poppy are a simple, reliable and well-defined model system to investigate the molecular and metabolic regulation of benzylisoquinoline alkaloid biosynthesis, and to evaluate the genetic engineering potential of these important medicinal plants.

Alkaloids↗
PubMed1996

An antibiotic-binding motif of an RNA fragment derived from the A-site-related region of Escherichia coli 16S rRNA.

A small RNA derived from the decoding region of Escherichia coli 16S rRNA can bind to antibiotics of aminoglycosides (neomycin and paromomycin) that act on the small ribosomal subunit [Purohit,P. and Stern,S. (1994) Nature, 370, 659-662]. In the present study, the P-site subdomain was removed from this decoding region RNA to construct a 27mer RNA (designated as ASR-27), which includes the A-site-related region (positions 1402-1412 and 1488-1497) of 16S rRNA. Footprint experiments with dimethyl sulfate as a chemical probe indicated that the ASR-27 RNA can interact with the neomycin family in the same manner as the decoding region RNA. A mutagenesis analysis of the ASR-27 RNA revealed that paromomycin binding of ASR-27 involves the C1407.G1494 and C1409-G1491 base pairs, and the internal loop comprising A1408 and the nucleotides in positions 1492-1493, located between the two C.G base pairs. In addition, a G or U in position 1495, and base pairing between positions 1405 and 1496 are also involved. These structural features were found in a viral RNA element, the Rev-binding site of human immunodeficiency virus type-1, which may explain why neomycin can bind to this viral RNA.

Aminoglycosides↗
PubMed1997

Cryptosporidiosis in Houston, Texas. A report of 95 cases.

Cryptosporidiosis is an important cause of diarrhea. We identified 95 patients with cryptosporidiosis over a 6-year period in our county hospital system, including 9 children and 86 adults infected with the human immunodeficiency virus (HIV). Risk factors included male-to-male sexual practices and Hispanic race. Diarrhea, weight loss, and gastrointestinal complaints were the most common symptoms at presentation. Among the HIV-infected adults, 20 (23%) developed biliary tract disease. Biliary involvement was associated with low CD4 counts. Treatment with paromomycin and antimotility agents was effective in reducing diarrheal symptoms in 54 of 70 (77%) patients with the acquired immunodeficiency syndrome (AIDS), although there was a high rate of relapse. Paromomycin did not prevent the development of biliary disease. Biliary disease responded to cholecystectomy or sphincterotomy with stent placement. Though often a cause of morbidity, cryptosporidiosis was only rarely the cause of death, even among patients with HIV. Cryptosporidiosis continues to be an important medical problem even in developed-countries. Current methods of prevention and treatment are suboptimal.

AIDS-Related Opportunistic Infections↗
PubMed1985

Role of gastrointestinal tract and liver in acetate metabolism in rat and man.

Net acetate uptake/release by various tissues was studied in vivo in fed, starved and Paromomycin-treated rats and in patients with cirrhosis of the liver. In humans the portal vein, hepatic vein and hepatic arterial blood flow rates were determined simultaneously. In rats acetate is only intestinally produced and released into the portal vein. Intestinal production is decreased by 33% in starved and Paromomycin-treated rats compared to fed animals. Portal vein hepatic vein acetate differences are linearly related to the portal vein acetate concentration (r = 0.92). Acetate uptake from the portal vein by the liver was found when the portal venous concentration exceeded 180 mumol l-1. In humans the hepatic net acetate uptake from the portal vein/net acetate release into the hepatic vein, measured as mmol min-1, is linearly related to the portal vein acetate concentration (r = 0.96). The data indicate that the liver may homeostatically regulate the systemic acetate concentration in rat and man.

Acetates↗
PubMed1985

In vitro susceptibilities of 25 Giardia lamblia isolates of human origin to six commonly used antiprotozoal agents.

The role drug resistance plays in the occurrence of chronic and recurrent giardiasis has not been established. Extensive data on the susceptibility to antimicrobial agents of living Giardia spp. trophozoites from human origin are lacking. We have determined with a macrodilution method in semisolid medium the in vitro susceptibility of 25 Giardia lamblia isolates, all obtained by routine cultivation of the duodenal fluid of children to six commonly used antiprotozoal drugs. The results showed tinidazole to be the most active drug (all isolates have MICs of less than or equal to 0.5 micrograms/ml). Metronidazole was equally active on all but one isolate, for which an MIC between 0.5 and 1 micrograms/ml was found. Furazolidone was the most active nonimidazole compound tested. More than 50% of the isolates were very susceptible to paromomycin, pyrimethamine, and chloroquine. Two of the strains presented an MIC for paromomycin higher than 10 micrograms/ml, and six strains needed more than 50 micrograms of pyrimethamine per ml to be inhibited. Decreased susceptibility of several of the isolates to different agents appears to be linked.

Animals↗
PubMed2005

Application of quantitative real-time reverse transcription-PCR in assessing drug efficacy against the intracellular pathogen Cryptosporidium parvum in vitro.

We report here on a quantitative real-time reverse transcription-PCR (qRT-PCR) assay for assessing drug efficacy against the intracellular pathogen Cryptosporidium parvum. The qRT-PCR assay detects 18S rRNA transcripts from both parasites, that is, the cycle threshold for 18S rRNA from parasites (C(T)([P18S])) and host cells (C(T)([H18S])), and evaluates the relative expression between parasite and host rRNA levels (i.e., deltaC(T) = C(T)([P18S]) - C(T)([H18S])) to minimize experimental and operational errors. The choice of qRT-PCR over quantitative PCR (qPCR) in this study is based on the observations that (i) the relationship between the logarithm of infected parasites (log[P]) and the normalized relative level of rRNA (deltadeltaC(T)) is linear, with a fourfold dynamic range, by qRT-PCR but sigmoidal (nonlinear) by qPCR; and (ii) the level of RNA represents that of live parasites better than that of DNA, because the decay of RNA (99% in approximately 3 h) in dead parasites is faster than that of DNA (99% in approximately 24 to 48 h) under in vitro conditions. The reliability of the qRT-PCR method was validated by testing the efficacies of nitazoxanide and paromomycin on the development of two strains of C. parvum (IOWA and KSU-1) in HCT-8 cells in vitro. Both compounds displayed dose-dependent inhibitions. The observed MIC50 values for nitazoxanide and paromomycin were 0.30 to 0.45 micro/ml and 89.7 to 119.0 microg/ml, respectively, comparable to the values reported previously. Using the qRT-PCR assay, we have also observed that pyrazole could inhibit C. parvum development in vitro (MIC50 = 15.8 mM), suggesting that the recently discovered Cryptosporidium alcohol dehydrogenases may be explored as new drug targets.

Animals↗
PubMed2005

Inhibitory activities of epidermal growth factor receptor tyrosine kinase-targeted dihydroxyisoflavone and trihydroxydeoxybenzoin derivatives on Sarcocystis neurona, Neospora caninum, and Cryptosporidium parvum development.

Several gene sequences of parasitic protozoa belonging to protein kinase gene families and epidermal growth factor (EGF)-like peptides, which act via binding to receptor tyrosine kinases of the EGF receptor (EGFR) family, appear to mediate host-protozoan interactions. As a clue to EGFR protein tyrosine kinase (PTK) mediation and a novel approach for identifying anticoccidial agents, activities against Sarcocystis neurona, Neospora caninum, and Cryptosporidium parvum grown in BM and HCT-8 cell cultures of 52 EGFR PTK inhibitor isoflavone analogs (dihydroxyisoflavone and trihydroxydeoxybenzoine derivatives) were investigated. Their cytotoxicities against host cells were either absent, mild, or moderate by a nitroblue tetrazolium test. At concentrations ranging from 5 to 10 microg/ml, 20 and 5 analogs, including RM-6427 and RM-6428, exhibited an in vitro inhibitory effect of > or = 95% against at least one parasite or against all three, respectively. In immunosuppressed Cryptosporidium parvum-infected Mongolian gerbils orally treated with either 200 or 400 mg of agent RM-6427/kg of body weight/day for 8 days, fecal microscopic oocyst shedding was abolished in 6/10 animals (P of <0.001 versus untreated controls) and mean shedding was reduced by 90.5% (P of <0.0001) and 92.0% (P of <0.0001), respectively, higher levels of inhibition than after nitazoxanide (200 mg/kg/day for 8 days) or paromomycin (100 mg/kg/day for 8 days) treatment (55.0%, P of <0.001, and 17.5%, P of >0.05, respectively). After RM-6427 therapy (200 mg/kg/day for 8 days), the reduction in the ratio of animals with intracellular parasites was nearly significant in ileum (P = 0.067) and more marked in the biliary tract (P < 0.0013) than after nitazoxanide or paromomycin treatment (0.05 < P < 0.004). RM-6428 treatment at a regimen of 400 mg/kg/day for 12 days inhibited oocyst shedding, measured using flow cytometry from day 4 (P < 0.05) to day 12 (P < 0.02) of therapy, when 2/15 animals had no shedding (P < 0.0001) and 11/15 were free of gut and/or biliary tract parasites (P < 0.01). No mucosal alteration was microscopically observed for treated or untreated infected gerbils. To our knowledge, this report is the first to suggest that the isoflavone class of agents has the potential for anticoccidial therapy.

Animals↗
PubMed1975

Antibiotic G418, a new micrommomospora-produced aminglycoside with activity apainst protozoa and helminths: antiparasitic activity.

Antibiotic G-418 was shown to be superior to paromomycin and metronidazole in cecal amoebiasis. Of particular interest was the high degree of activity seen with a relatively short treatment at low levels. Although the antibiotic was trichomonacidal in vitro at low levels, in vivo results indicated that at levels tested the antibiotic did not always affect cures. The antibiotic appears to have promise as an anticestode agent, being more active than paromomycin against Hymenolepis nana and active as a single oral dose at low levels against Taenia spp.

Aminoglycosides↗
PubMed2006

Drug resistance in leishmaniasis.

Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

Animals↗
PubMed1985

Characterization of Saccharomyces cerevisiae mutants supersensitive to aminoglycoside antibiotics.

We describe mutants of Saccharomyces cerevisiae that are more sensitive than the wild type to the aminoglycoside antibiotics G418, hygromycin B, destomycin A, and gentamicin X2. In addition, the mutants are sensitive to apramycin, kanamycin B, lividomycin A, neamine, neomycin, paromomycin, and tobramycin--antibiotics which do not inhibit wild-type strains. Mapping studies suggest that supersensitivity is caused by mutations in at least three genes, denoted AGS1, AGS2, and AGS3 (for aminoglycoside antibiotic sensitivity). Mutations in all three genes are required for highest antibiotic sensitivity; ags1 ags2 double mutants have intermediate antibiotic sensitivity. AGS1 was mapped 8 centimorgans distal from LEU2 on chromosome III. Analyses of yeast strains transformed with vectors carrying antibiotic resistance genes revealed that G418, gentamicin X2, kanamycin B, lividomycin A, neamine, and paromomycin are inactivated by the Tn903 phosphotransferase and that destomycin A is inactivated by the hygromycin B phosphotransferase. ags strains are improved host strains for vectors carrying the phosphotransferase genes because a wide spectrum of aminoglycoside antibiotics can be used to select for plasmid maintenance.

Aminoglycosides↗